Beta-blockers in psychiatry: Pharmacokinetic interactions of antipsychotics with CYP2D6- HPLC as a quantitative method for analysis in TDM

Introduction and Aims: Approximately 8% of the schizophrenic patients, whose blood was tested for clozapine, olanzapine and quetiapine in the therapeutic drug monitoring (TDM) laboratory in Regensburg, are co-medicated with beta-blockers. The three antipsychotic drugs and beta-blockers may be metabolized by the same cytochrome-P450-isoenzyme (CYP2D6) which is inhibited by representatives of both substance classes. Inhibition of the enzyme slows down the metabolism of the drugs in the patient, eventually resulting in a supratherapeutic drug concentration, thereby increasing the risk of side effects. We were interested in cross-effects of these drug-drug-interactions for both partners. Therefore, we developed a high performance liquid chromatography (HPLC) assay to simultaneously detect and quantify beta-blockers, antipsychotics and their metabolites. Methods: HPLC with ultraviolet detection used a Phenomenex Luna Phenyl-Hexyl analytical column, a linear gradient of phosphate buffered methanol and acetonitrile. Results: The HPLC method allowed TDM of 7 beta-blockers (atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, propranolol und timolol), 3 antipsychotics and their metabolites (clozapine, norclozapine, olanzapine, norolanzapine und quetiapine) in serum. This method enabled determination of all substances within 18 minutes. The use of a restricted access material (RAM) column enabled us to analyse the samples without time-consuming solid-phase or liquid-liquid extraction. Conclusions: Because of short analysis time and simple handling, the developed HPLC protocol permits the use of the method for routine application in clinical laboratories. TDM of these drugs should lead to more individualized therapy, improved drug-safety and reduced treatment costs.